2. Academic Validation
  3. Discovery of Zharp1-163 as a dual inhibitor of ferroptosis and necroptosis for the treatment of inflammatory disorders and kidney injury

Discovery of Zharp1-163 as a dual inhibitor of ferroptosis and necroptosis for the treatment of inflammatory disorders and kidney injury

  • Cell Death Discov. 2025 Aug 28;11(1):413. doi: 10.1038/s41420-025-02693-5.
Yuting Ji # 1 2,  Shujing Du # 1,  Jingjing Li # 1,  Haikuo Ma # 3,  Xinhui Wang 1,  Yongjin Hao 3,  Zhanhui Li 3,  Haohao Lu 1,  Hao Liu 4,  Chengkui Yang 5,  Xiaohu Zhang 6,  Sudan He 7
Affiliations

Affiliations

  • 1 State Key Laboratory of Common Mechanism Research for Major Diseases, and Key Laboratory of Synthetic Biology Regulatory Elements, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, 215123, Jiangsu, China.
  • 2 School of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangsu, China.
  • 3 Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, China.
  • 4 School of Chemistry, Chemical Engineering and Life Science, Wuhan University of Technology, Wuhan, 430070, Hubei, People's Republic of China.
  • 5 State Key Laboratory of Common Mechanism Research for Major Diseases, and Key Laboratory of Synthetic Biology Regulatory Elements, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, 215123, Jiangsu, China. yangck222@163.com.
  • 6 Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, China. xiaohuzhang@suda.edu.cn.
  • 7 State Key Laboratory of Common Mechanism Research for Major Diseases, and Key Laboratory of Synthetic Biology Regulatory Elements, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, 215123, Jiangsu, China. hesd@ism.pumc.edu.cn.
  • # Contributed equally.
PMID: 40877228 DOI: 10.1038/s41420-025-02693-5
Abstract

Dysregulation of cell death plays a critical role in the onset and progression of numerous human diseases. Distinct forms of regulated cell death, such as Necroptosis and Ferroptosis, have been implicated in the pathogenesis of various conditions, including neurodegenerative disorders and acute kidney injury. Strategies that concurrently target both Necroptosis and Ferroptosis present significant potential for improving therapeutic outcomes. In this study, we identified Zharp1-163 as a dual inhibitor of Ferroptosis and Necroptosis in both human and mouse species. Zharp1-163 effectively blocks Ferroptosis by reducing Reactive Oxygen Species (ROS) levels and inhibits Necroptosis by potently and selectively targeting RIPK1 kinase activity. In vivo, Zharp1-163 markedly attenuated TNF-α-induced systemic inflammatory syndrome, including the prevention of TNF-α-induced mortality and hypothermia in mice. Notably, Zharp1-163 significantly alleviated acute kidney injury associated with both Necroptosis and Ferroptosis in models induced by cisplatin treatment and ischemia-reperfusion. Collectively, our findings establish Zharp1-163 as a dual-action inhibitor capable of effectively suppressing both Ferroptosis and Necroptosis. These findings highlight its great potential in the treatment of diseases associated with these cell death pathways, such as kidney disease.

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